The dawning of the age of genomic medicine, finally

LA JOLLA, California (Reuters) - When President Bill Clinton
announced in 2000 that Craig Venter and Dr. Francis Collins of
the National Human Genome Research Institute had succeeded in
mapping the human genome, he solemnly declared that the
discovery would "revolutionize" the treatment of virtually all
human disease.

The expectation was that this single reference map of the 3
billion base pairs of DNA - the human genetic code - would
quickly unlock the secrets of Alzheimer's, diabetes, cancer and
other scourges of human health.

As it turns out, Clinton's forecast was not unlike President
George Bush's "mission accomplished" speech in the early days of
the Iraq war, said Dr. Eric Topol of Scripps Translational
Science Institute, which is running a meeting on the Future of
Genomic Medicine here March 6-7.

Thirteen years after Clinton's forecast, even Venter
acknowledges that mapping the human genome has had little
clinical impact. "Yes, there's been progress, but we all would
have hoped it would have been more rapid," he said in an
interview in his offices this week.

But that is finally changing.

"We are at an inflection point," said Collins, who now
directs the National Institutes of Health. In a telephone
interview, he said he never expected an "overnight, dramatic
impact" from sequencing the human genome, in part because of
cost.

Recently, a combination of lower-cost sequencing technology
and a growing list of wins in narrow corners of medicine are
starting to show that genomic medicine is on the verge of
delivering on at least some of those early claims.

Recent advances in sequencing have been "pretty stunning"
and genomics is "just on the threshold" of delivering results,
Venter told Reuters.

Although much is left to be learned about the genome,
scientists believe knowing a person's genetic code will lead to
highly personalized treatments for cancer, better predictions
for diseases in babies and help unlock the puzzle of mysterious
genetic diseases that currently go undiagnosed and untreated.

Venter is staking his latest entrepreneurial venture on that
expectation. Earlier this week, he announced formation of a new
company, Human Longevity Inc., to undertake a massive project:
sequencing 40,000 human genomes a year in a search for new
therapies to preserve health and fight off diseases, including
cancer, heart disease and Alzheimer's.

To do that, Human Longevity will use two HiSeq X Ten
machines and has an option to buy three more. The sequencers,
made by Illumina Inc., can map a single genome for as little as
$1,000.

Breaching the $1,000 genome could prove to be a watershed.
At that cost, said Illumina Chief Executive Jay Flatley,
ambitious projects like Venter's are economically feasible and
clinical results more achievable.

"We've still only scratched the surface of what the genome
holds," he said. "What we need to do now is get hundreds of
thousands to millions of genomes in databases with clinical
information," he added.

MAKING A DIFFERENCE

Advances in sequencing equipment and the advent of
next-generation sequencing has transformed the work Dr.
Elizabeth McNally does as director of the Cardiovascular
Genetics Clinic at the University of Chicago.

In seven short years, she said, her group has gone from
testing just one gene at a time to testing 60 to 70 genes and
she is moving quickly into whole genome sequencing.

McNally points to the case of Jeanne Sambrookes - a patient
who is alive today because of these advances.

As a child, Sambrookes often noticed the distinct, hunched
posture of her mother, her aunt and her grandmother as they
struggled to climb a flight of stairs.

Sambrookes had been very athletic as a young teen, but as
she matured, she noticed a heaviness in her legs. By age 20,
running left her tired. At 40, she needed a pacemaker, just like
her mother did at that age.

"I started thinking there is something to this," said
Sambrookes, now 56, who lives in Michigan City, Indiana.

After some dead ends, she found McNally, who cast a wide
net, testing for more than two dozen genes that could account
for Sambrookes' heart and muscle problems.

The culprit turned out to be a mutation in a gene called
Lamin that causes Limb-girdle muscular dystrophy. The disease
can cause weakness and wasting of the muscles between the
shoulders and knees. The mutation can also cause electrical
disturbances of the heart.

McNally recommended Sambrookes replace her pacemaker with an
implantable cardiac defibrillator that could protect against
sudden cardiac death.

That proved to be the right call. Last August, Sambrookes'
heart stopped three times. Each time, the defibrillator shocked
her back to life.

Although McNally uses panels of 70 to 80 genes in her
clinic, she has started experimenting with whole genomes. With
the reduced cost of gene mapping, whole gene sequencing is a
potentially cheaper, more powerful tool.

The reduced cost of mapping is cutting the cost of research,
too - another factor that could speed clinical outcomes.
McNally's team recently published a paper in the journal
Bioinformatics in which she used Beagle, a supercomputer housed
at Argonne National Laboratory, to analyze 240 full genomes in
about two days. Such an endeavor normally takes months.

"That dramatically decreases the cost associated with
analysis because we sped up the time," said McNally.

CORNERS OF MEDICINE

Dr. Jay Shendure, associate professor of Genome Sciences at
the University of Washington in Seattle, said the impact of gene
sequencing is beginning to emerge in specific areas - after a
startup period that was longer and narrower than expected.

"I do think there are these corners of medicine, which are
important ones, that may happen relatively quickly," he said.

A key example is the use of a pregnant woman's blood to see
if her fetus may have trisomies - chromosomal abnormalities
associated with Down syndrome and other disorders.

"Almost overnight, sequencing is in the process of taking
over as the primary means of screening for trisomies in at-risk
populations, and maybe eventually to everyone," Shendure said.

The clinical results are promising. A trial of Illumina's
test published last week in the New England Journal of Medicine
found about 3.6 percent of standard tests for trisomies had
false positive results, compared with 0.3 percent with
Illumina's Verify test.

That means fewer women would need to go through invasive
follow-up diagnostic tests using amniocentesis or chorionic
villus sampling, both of which can cause miscarriages.

If the tests become routine practice, Goldman Sachs analyst
Issac Ro estimates the market could reach $6 billion a year.

Venter's new company, Human Longevity, has picked cancer as
its first sequencing target. Working with the University of
California, San Diego, the company plans to sequence the
genomes, as well as the tumors, of every cancer patient treated
at UCSD's Moores Cancer Center.

Collins calls cancer a "disease of the genome" and notes
that genomics has revealed cancer to be a collection of
different mutations, all of which contribute to its growth.

Drug companies have responded with treatments that block
aberrant pathways, an approach called precision medicine.

"That's happened pretty quickly because of this window that
DNA sequencing has provided," said Collins.